Apparatus and material composition for permanent occlusion of a hollow anatomical structure

ABSTRACT

This invention relates to occlusion of a hollow anatomical structure by inserting an occluding device or occluding material into a hollow anatomical structure or surrounding native tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 60/605,843, filed Aug. 31, 2004. Theabove-referenced prior application is incorporated by reference hereinin its entirety and is hereby made a portion of this specification.

FIELD OF THE INVENTION

This invention relates to occlusion of a hollow anatomical structure byinserting an occluding device or occluding material into a hollowanatomical structure or surrounding native tissue.

BACKGROUND OF THE INVENTION

The preferred embodiments relate generally to a method and materialcomposition for introduction into a hollow anatomical structure (HAS)with particular relevance to the venous system in the lower extremities.The term “hollow anatomical structure” is a broad term and is used inits ordinary sense, including, without limitation, veins, arteries,gastric structures, coronary structures, pulmonary structures, tubularstructures associated with reproductive organs, and the like. Hollowanatomical structures particularly suited to occlusion by the methods ofpreferred embodiments include veins, preferably veins of the lowerextremities, especially veins in the leg.

The human venous system of the lower extremities consists essentially ofthe superficial venous system and the deep venous system withperforating veins connecting the two systems. The superficial systemincludes the long or great saphenous vein and the small saphenous vein.The deep venous system includes the anterior and posterior tibial veinswhich unite to form the popliteal vein, which in turn becomes thefemoral vein when joined by the short saphenous vein.

The venous system contains numerous one-way valves for directing bloodflow back to the heart. Venous valves are usually bicuspid valves, witheach cusp forming a sack or reservoir for blood. Retrograde blood flowforces the free surfaces of the cusps together to prevent continuedretrograde flow of the blood and allows only antegrade blood flow to theheart. When an incompetent valve is in the flow path, the valve isunable to close because the cusps do not form a proper seal andretrograde flow of the blood cannot be stopped. When a venous valvefails, increased strain and pressure occur within the lower venoussections and overlying tissues, sometimes leading to additional, distalvalvular failure. Two venous conditions or symptoms which often resultfrom valve failure are varicose veins and more symptomatic chronicvenous insufficiency.

The resulting condition is progressive and includes: dilation andtortuosity of the superficial veins of the lower limbs, unsightlydiscoloration, pain, swelling, and possibly ulceration. This failure canalso worsen deep venous reflux and perforator reflux. Current treatmentsof venous insufficiency include surgical procedures such as veinstripping, ligation, RF ablation, laser treatment, vein closure, andvein-segment transplant.

Vein stripping and vein-segment transplant are less-favored treatmentoptions. Vein stripping typically consists of tying off, or ligating,and removal of the saphenous vein. The ligation involves making anincision in the groin and using sutures outside the vein to tie it shut.When the veins are tied off and/or removed, blood flows through the deepveins and back to the heart. This surgery is generally done undergeneral or spinal anesthesia during a hospital stay or on an outpatientbasis, depending upon the extent of the procedure. Vein stripping isgenerally painful and requires a long recovery time. This procedure isless favored and outcomes can be poor. Procedures combining ligation andstripping are sometimes performed, but studies have shown they offerlittle advantage over stripping alone. Vein segment transplant has beenemployed in certain organ transplant procedures. However it is notgenerally employed in the superficial venous system in humans.

Ligation by ablation involves the cauterization or coagulation ofvascular lumina using thermal energy applied through a deliverycatheter, e.g., electrical energy applied through an electrode device(e.g., a radio frequency or RF device), energy delivered by regular andhigh-frequency ultrasound, or laser energy. An energy delivery device istypically introduced into the vein lumen and positioned so that itcontacts the vein wall. Once properly positioned, the RF, laser,ultrasound, or other energy is applied to the energy delivery device,thereby causing the vein wall to shrink in cross-sectional diameter. Areduction in cross-sectional diameter, for example, from 5 mm (0.2 in)to 1 mm (0.04 in), significantly reduces the flow of blood through thevein and results in an effective ligation. Though not required foreffective ligation, the vein wall can completely collapse, therebyresulting in a full-lumen obstruction that blocks the flow of bloodthrough the vein.

SUMMARY OF THE INVENTION

Even with technological advances in the various methods of occlusion,there is a need for a less invasive or non-thermal method for permanenttotal occlusion of hollow anatomical structures such as incompetentveins. Thus there is an opportunity and a need for less invasivetreatments and therapies for venous diseases in the lower extremities.The preferred embodiments provide materials and methods which can beemployed to occlude a hollow anatomical structure. Preferably, abioresorbable (e.g., breaks down and is absorbed by a cell, tissue, orother mechanism within the body) or bioabsorbable (similar tobioresorbable) material is employed to occlude the hollow anatomicalstructure. Alternatively, a bioerodable (e.g., erodes or degrades overtime by contact with surrounding tissue fluids, through cellularactivity or other physiological degradation mechanisms), biodegradable(e.g., degrades over time by enzymatic or hydrolytic action, or othermechanism in the body), or dissolvable material is employed. Each ofthese terms is interpreted to be interchangeable. In certainembodiments, a biocompatible material that is not bioabsorbable,bioerodable, biodegradable, or dissolvable is employed. Thebioabsorbable material is preferably placed in the hollow anatomicalstructure by a minimally invasive method which can be employed forprecisely locating the material within the target lumen.

While the methods and materials of preferred embodiments areparticularly preferred for use in occluding veins of the lowerextremities, they can be employed in occluding other hollow anatomicalstructures, including, but not limited to: blood vessels such asperforating veins which connect the superficial veins to the deep veinsin the leg, truncal superficial veins of the leg (e.g., great saphenousvein, short saphenous vein, and the like), superficial tributary veinsof the leg, telangiectasia, internal spermatic veins (varicoceles),ovarian veins, gonadal veins, hemorrhoidal vessels, esophageal varices,fallopian tubes, vas deferens, arteriovenous malformations,arteriovenous fistula networks, aortic aneurysm excluded lumens post AAAgraft placement, lumbar arteries, feeding vessels into the aorta toprevent abdominal aortic aneurysm (AAA) graft endoleaks, treatment ofsleep apnea, and the like.

Accordingly, in a first aspect an apparatus for occluding a hollowanatomical structure in a patient is provided, the apparatus comprisinga bioresorbable material, wherein, upon placement in a hollow anatomicalstructure, the material blocks fluid flow through the hollow anatomicalstructure to a degree sufficient to induce a durable occlusion of thehollow anatomical structure.

In an embodiment of the first aspect, the hollow anatomical structure isa blood vessel.

In an embodiment of the first aspect, the material comprises a viscousflow-blocking material.

In an embodiment of the first aspect, the material is configured to beinjectable.

In an embodiment of the first aspect, the material is configured to besufficiently viscous to maintain its position in a hollow anatomicalstructure with an inside diameter greater than or equal to about 2, 3,4, or 5 mm or more. The hollow anatomical structure can comprise a bloodvessel.

In an embodiment of the first aspect, the material is configured to besufficiently flowable to flow into a hollow anatomical structure with aninside diameter less than or equal to about 1 or 2 mm. The hollowanatomical structure can comprise a blood vessel.

In an embodiment of the first aspect, the material is selected from thegroup consisting of collagen, fibrinogen, fibronectin, vitronectin,laminin, thrombin, gelatin, and mixtures thereof, so as to substantiallyblock flow into the hollow anatomical structure by causing clotting andfibrotic tissue occlusion.

In an embodiment of the first aspect, the material is curable in situupon placement in the hollow anatomical structure.

In an embodiment of the first aspect, the material is configured toundergo a viscosity change in situ after placement in the hollowanatomical structure. The viscosity change can be manifested by at leastone process selected from the group consisting of crosslinking, curing,hardening, thickening, and swelling.

In an embodiment of the first aspect, the material is in a form of asponge. The sponge can have a porous, open-cell configuration. In apreferred embodiment, the sponge has an average pore diameter greaterthan or equal to about 50 microns, and the porous, open-cellconfiguration promotes cellular ingrowth upon placement of the sponge inthe hollow anatomical structure. Alternatively, the sponge can have anon-porous, closed-cell configuration.

In an embodiment of the first aspect wherein the material is in a formof a sponge, the sponge expands radially in situ to span a cross sectionof the hollow anatomical structure.

In an embodiment of the first aspect wherein the material is in a formof a sponge, the sponge further comprises an additive selected from thegroup consisting of sclerosant, venoconstrictor, anti-bacterial agent,drug, anti-inflammatory agent, anti-infective agent, anesthetic,pro-inflammatory agent, cell proliferative agent, tretinoin,procoagulant, and combinations thereof. The procoagulant can be selectedfrom the group consisting of collagen, fibrinogen, fibronectin,vitronectin, laminin, thrombin, gelatin, and mixtures thereof.

In an embodiment of the first aspect, the material is in a form of aplug. The plug can be non-porous, or configured to maintain across-sectional size upon placement in the hollow anatomical structure,or is formed in situ in the hollow anatomical structure, or ispre-formed before being placed in the hollow anatomical structure.

In an embodiment of the first aspect, the material is in a form of asheet, the apparatus further comprising an adhesive disposed on at leastone of a first side of the sheet and a second side of the sheet.

In an embodiment of the first aspect, the material is in a form of atube, the apparatus further comprising an adhesive disposed on at leastone of an outer surface of the tube and an inner surface of the tube.

In an embodiment of the first aspect, the material is in a form of arolled sheet prior to insertion into the hollow anatomical structure,the apparatus further comprising an adhesive disposed on at least one ofa first side of the sheet and a second side of the sheet, the sheethaving an inserted configuration in which the sheet is at leastpartially unrolled.

In an embodiment of the first aspect, the material comprises a rod whichis configured to swell upon placement in the hollow anatomicalstructure. The rod can comprise a hydrogel.

In a second aspect, a method for occluding a hollow anatomical structurein a patient is provided, the method comprising the step of placing anoccluding material at an occlusion site, whereby an occlusion is formedin the hollow anatomical structure.

In an embodiment of the second aspect, the method further comprises astep of identifying an occlusion site, wherein the step of identifyingis conducted before the step of placing an occluding material at theocclusion site.

In an embodiment of the second aspect, the occluding material comprisesa tissue adhesive. The tissue adhesive can be a cyanoacrylate adhesive.Alternatively, the tissue adhesive can be selected from the groupconsisting of collagen, fibrinogen, fibronectin, vitronectin, laminin,thrombin, gelatin, and mixtures thereof.

In an embodiment of the second aspect, the method further comprises astep of reducing an interior cross-sectional area of the hollowanatomical structure. The area can be reduced by applying a compressionto the hollow anatomical structure or by applying a vacuum to aninterior of the hollow anatomical structure. In a preferred embodiment,the hollow anatomical structure is a blood vessel, and the area isreduced by administering a venoconstrictor to the patient. The step ofreducing an interior cross-sectional area can be conducted before thestep of placing an occluding fluid material at the site, or after thestep of placing an occluding material at the site.

In an embodiment of the second aspect, the occluding site is near atleast one valve in a vein.

In an embodiment of the second aspect, the occluding fluid materialcomprises a hydrogel, wherein the hydrogel expands in situ to occludethe hollow anatomical structure.

In an embodiment of the second aspect, the step of placing an occludingmaterial comprises the steps of placing at least one temporary occludingdevice in the hollow anatomical structure adjacent to the site; placingan occluding fluid material at the site adjacent to the temporaryoccluding device; solidifying or curing the occluding fluid material,whereby an occlusion is formed in the hollow anatomical structure; andremoving the temporary occluding device.

In an embodiment of the second aspect, the step of placing an occludingmaterial comprises the steps of placing at least one occluding device inthe hollow anatomical structure adjacent to the site, whereby acontiguous occlusion is formed; placing an occluding fluid material atthe site adjacent to the occluding device; and solidifying or curing theoccluding fluid material, whereby an occlusion is formed in the hollowanatomical structure.

In an embodiment of the second aspect, the occluding material forms acontiguous occlusion.

In an embodiment of the second aspect, the occluding fluid material isplaced at at least two separate locations, forming two noncontiguousocclusions. A sclerosant can be placed between the two noncontiguousocclusions.

In an embodiment of the second aspect, the occlusion site is interior tothe hollow anatomical structure.

In an embodiment of the second aspect, the occlusion site is exterior tothe hollow anatomical structure.

In an embodiment of the second aspect, the hollow anatomical structureis a vein, and the step of placing an occluding material at the sitecomprises the step of placing a material in a perivenous spacesurrounding the vein at the occlusion site, whereby an occlusion isformed in the vein. The material can be shrinkable, and the occlusioncan be formed by shrinking the material. The material can be collagen,and the step of shrinking can comprise heating the collagen.

In an embodiment of the second aspect, the occluding material comprisescollagen, preferably in the form of a plug or a sponge.

In an embodiment of the second aspect, the occluding material comprisesan alpha-hydroxy acid, preferably in the form of a plug or a sponge.

In an embodiment of the second aspect, the occluding material comprisesa therapeutic agent selected from the group consisting ofanti-inflammatory agents, anti-infective agents, anesthetics,pro-inflammatory agents, cell proliferative agents, tretinoin,procoagulants, and combinations thereof.

In an embodiment of the second aspect, the occluding material is in afluid form that cures in situ to form an occlusion in the hollowanatomical structure.

In an embodiment of the second aspect, the occluding material changesviscosity in situ to form an occlusion in the hollow anatomicalstructure

In an embodiment of the second aspect, the occluding material is placedin the hollow anatomical structure through a needle or a catheter.

In an embodiment of the second aspect, the hollow anatomical structureis a vein, and the method further comprises the step of placing asclerosant in the vein.

In an embodiment of the second aspect, the occluding material comprisesa sclerosant, optionally in combination with dimethyl sulfoxide.

In an embodiment of the second aspect, the occluding material iscombined with a sclerosant. The occluding material can be in a form of asponge, and the sclerosant can be contained on or within the sponge.

In an embodiment of the second aspect, the occlusion is a partialocclusion.

In an embodiment of the second aspect, the occlusion is a completeocclusion.

In an embodiment of the second aspect, the hollow anatomical structureis part of the superficial human venous system of the lower extremities.

In an embodiment of the second aspect, the hollow anatomical structureis a vein selected from the group consisting of the great saphenousvein, the small saphenous vein, a perforating vein which connectssuperficial veins to deep veins in the leg, and a superficial tributaryvein of the leg.

In an embodiment of the second aspect, the hollow anatomical structureis selected from the group consisting of telangiectasia, internalspermatic vein, ovarian vein, gonadal vein, hemorrhoidal vessel,esophageal varices, fallopian tube, vas deferens, arteriovenousmalformation, arteriovenous fistula network, aortic aneurysm excludedlumens post abdominal aortic aneurysm graft placement, lumbar artery,and feeding vessel into the aorta.

In an embodiment of the second aspect, the step of identifying anocclusion site in a hollow anatomical structure utilizes anidentification method selected from the group consisting of ultrasound,compression, palpation, endoscopy, fluoroscopy, and use of contrastmedia.

In a third aspect, a kit for use in forming an occlusion in a hollowanatomical structure in a patient is provided, the kit comprising anoccluding material comprising a biocompatible injectable fluid orbioabsorbable injectable fluid, and instructions for placing anoccluding material at the site, whereby an occlusion is formed in thehollow anatomical structure. The kit can further include instructionsfor identifying an occlusion site.

In an aspect of the third embodiment, the kit further comprises adelivery device for placing the occluding material at the occlusionsite, the delivery device comprising a needle or a catheter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The following description and examples illustrate a preferred embodimentof the present invention in detail. Those of skill in the art willrecognize that there are numerous variations and modifications of thisinvention that are encompassed by its scope. Accordingly, thedescription of a preferred embodiment should not be deemed to limit thescope of the present invention.

Methods for occluding a hollow anatomical structure in a patient orsubject using an occluding device or occluding material are provided.The terms “subject” and “patient” as used herein, refer to animals, suchas mammals. For example, mammals contemplated by the include humans,primates, dogs, cats, sheep, cattle, goats, pigs, horses, mice, rats,rabbits, guinea pigs, and the like. The terms “subject” and “patient”are used interchangeably.

The terms “occluding device” and “occluding material” as used herein,are broad terms and are used in their ordinary sense, including, withoutlimitation, a substance or device that is capable of occluding orcausing occlusion of a hollow anatomical structure. Occlusion can be“acute” (i.e., complete blockage, or 100% volume filling) or “partial”(i.e., less than complete blockage, or less than 100% volume filling).Occlusion can include blocking or inhibiting blood flow to a degreesufficient to relieve patient symptoms, inducing clotting or tissueingrowth, causing a durably fibrotic occlusion, or occluding in otherfashions, either directly or indirectly. Occluding materials oroccluding devices can be formed or fabricated ex situ, or formed in situ(e.g., by curing of a prepolymer or uncured polymer). Occluding can beachieved directly by the occluding material or induced indirectly by theoccluding material. The term “occluding material” as employed herein,includes prepolymers, uncured polymers, unsolidifed materials, as wellas occluding materials inserted into a patient in precured or solidifiedform. Bioabsorbable materials are particularly preferred occludingmaterials.

Occluding can include, but is not limited to, blocking by insertion of aplug or other structure into the hollow anatomical structure thatprevents or inhibits flow therethrough, adhering opposite walls of thehollow anatomical structure together so as to prevent or inhibit flowtherethrough, compressing the walls of the hollow anatomical structuretogether so as to prevent or inhibit flow therethrough, or initiating aphysiological reaction to an applied force or substance (e.g., energy,chemicals, drugs, physical contact, pressure or the like) that causesflow through the hollow anatomical structure to be inhibited orprevented (e.g., formation of an organized thrombus, or growth ofconnective tissue). Occlusion can be immediate, or onset of occlusioncan be delayed. Occlusion can be partial (permitting a reduced flowthrough the hollow anatomical structure) or complete (permitting no flowthrough the hollow anatomical structure). Occlusion can be permanent ortemporary. Occlusion can result in physical change or damage to thehollow anatomical structure (e.g., sclerosis), or can block the hollowanatomical structure without substantial physical change (e.g., abiocompatible plug). The mechanisms by which occlusion can occur includebut are not limited to formation of a wound or damage to tissue,expansion of the occluding device or occluding material, release of achemical (e.g., a sclerosant or inflammatory agent) from the occludingdevice or occluding material, venoconstriction, compression, andligation. Other mechanisms, forms, and effects of occlusion will beappreciated by those of skill in the art.

Occluding Materials

The use of organic materials and polymers in medical application iswidely known and accepted in the medical field. Representative examplesof such materials include absorbable materials composed of purifiedconnective tissue (collagen) derived from the serosal layer of cattle(bovine) intestines, as well as synthetic materials such as VICRYL™polymer manufactured by Johnson & Johnson/Ethicon. Further advances inbiodegradable and bioabsorbable materials have led to breakthroughdevelopments in the stent field with the primary intention ofmaintaining patency after placement. Stents have been developed forcoronary artery disease (e.g., plaque in the arteries, associated withmyocardial infarction/heat attack), or aneurisms. Stents have also beenemployed in urology to maintain an opening in a urethra that's swollenshut, for example, as a complication of benign prostate hyperplasty.Stent grafts with bioactive coatings are described in U.S. Publ. No.2002/0065546 A1 to Machan, et al., the contents of which are herebyincorporated by reference in their entirety.

Any suitable material can be employed to occlude the hollow anatomicalstructure. Generally, non-rigid materials are preferred. However, incertain embodiments it can be advantageous to employ a rigid material.The materials are preferably flexible or deformable, or in fluid form,such as a highly viscous fluid. A fluid that solidifies or cures to asolid form (for example, a prepolymer) can also be employed. Thematerial is preferably bioabsorbable materials that can be fabricatedinto a desired form (e.g., sponge, matrix, powder, plug, rod, fibrousmass, or the like) for insertion into the hollow anatomical structure,or which can be formed in place (e.g., inserted in fluid or other form,then cured by light, heat, exposure to physiological conditions (pH),water, bodily fluids, or solvent). A suitable size and shape of thematerial is selected according to the hollow anatomical structure to beoccluded. In an area of low venous blood flow, a structure which isslightly larger than the inner diameter of the vessel is generallypreferred. For applications wherein permanent occlusion of vessels(e.g., arteries) subjected to high pressures is desired, a structure ofhigher compression modulus and larger expanded size relative to theinner diameter of the lumen is typically preferred. The shape of thematerial can also be tailored to fit the need of a given application. Aspherical, cylindrical, rod, conical, oval, rolled, helical, coiled orother shape can be employed, as desired. The shape can be solid orporous. The shape can comprise a composite of two or more materials withdifferent bioabsorption rates, different biodegradation rates,solubilities, porosities, strengths, rigidities, or the like. Likewise,materials of different forms (liquid, solid, gel, fibrous mass, and thelike) can be used in combination.

The occluding device or material is preferably a bioabsorbable material.Bioabsorbable materials employed to occlude a hollow anatomicalstructure are preferably solid and flexible. The bioabsorbable materialcan be in the form of a sponge or foam, or can comprise a contiguousblock of material lacking void spaces. The bioabsorbable material cancomprise a single component, or can be fabricated as a compositematerial constructed from two or more components. In one embodiment, theoccluding device comprises a thin sheet with adhesive on both sides.Alternatively, adhesion between the walls of the hollow anatomicalstructure can be provided by blood clotting or blood clotting promotingagents, rather than a conventional tissue adhesive.

In embodiments wherein an adhesive sheet is employed, the sheet isplaced in the hollow anatomical structure and adheres opposite walls ofthe hollow anatomical structure together when external compression orvacuum is applied to the hollow anatomical structure. Alternatively, theoccluding device can include a mechanical or chemical abrasive. Theabrasive causes endothelial cell destruction when it contacts the wallsof the hollow anatomical structure, facilitating the occlusion process.Alternatively, the bioabsorbable material can be fabricated such that itpossesses an abrasive surface. The bioabsorbable material can befabricated to exhibit micromotion in situ, to facilitate abrasionagainst the walls of the hollow anatomical structure. Preferably, theoccluding device or occluding material provokes an inflammatoryresponse, causing a wound. This initiates a fibrotic response from theremaining tissue, or initiates the body's natural healing response, orcauses the wound healing cascade to initiate. The degree of inflammatoryresponse can be controlled by altering material properties, the amountof material, amount of active agent. However, in other embodiments itcan be preferred that the occluding device or occluding material notprovoke an inflammatory response.

Bioabsorbable materials suitable for use in preferred embodimentspreferably exhibit an absorption period of from about three days or lessto one year or more, preferably from about 1 week to 2, 3, 4, 5, 6, 7,8, 9, 10, or 11 months, more preferably from about 1 week to about 2, 3,4, 5, or 6 weeks. Rigid materials can be acceptable for use in thoseindications wherein the material does not cause pain upon movement orinhibit movement. When ease of movement is desirable (e.g., in theocclusion of veins in the lower extremities), the material is preferablyflexible. The material is preferably not excessively brittle if exposedto forces that could shatter it so as to destroy any occluding function.However, if external forces after placement are minimal, then materialswith some degree of brittleness can be suitable for use. For fluidoccluding materials, the viscosity is preferably low enough so as toenable placement of the material, e.g., by catheter or needle), but ispreferably high enough such that the material does not exhibit excessivemigration. In certain embodiments, it is desirable to employ a fluidmaterial that possesses a degree of “stickiness” or demonstratesadhesive properties.

Such materials can include naturally occurring materials or materialsderived from natural sources, or synthetic materials. Examples ofbiodegradable polymers which can be used include polylactides,polyglycolides, polycaprolactones, polyanhydrides, polyamides,polyurethanes, polyesteramides, polyorthoesters, polydioxanones,polyacetals, polyketals, polycarbonates, polyorthocarbonates,polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates,polyhydroxyalkanoates (PHAs), polyalkylene oxalates, polyalkylenesuccinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone,polyethylene glycol, polyhydroxycellulose, chitin, chitosan, andcopolymers, terpolymers, or combinations or mixtures of the abovematerials, with or without added components. Suitable biocompatible andbioabsorbable polymers are described in U.S. Pat. No. 6,423,085 toMurayama et al., and U.S. Pat. No. 6,676,971 to Goupil, et al., thecontents of which are hereby incorporated by reference in theirentirety. Proteins such as collagen, fibrinogen, fibronectin,vitronectin, laminin, thrombin, and gelatin can also be employed.

Other suitable materials include alpha-hydroxy acids, such aspolyglycolides, polylactides, and copolymers of lactic acid and glycolicacid). Poly(lactic-glycolic acid) (PLGA) is a suitable material. It is asynthetic absorbable copolymer of glycolide and lactide marketed underthe trade name VICRYL™ (a Polyglactin 910 manufactured by Ethicon, adivision of Johnson & Johnson of Somerset, N.J.). It is absorbed thoughenzymatic degradation by hydrolysis

Gelatin is an absorbable material often used in surgical procedures toarrest venous or oozing bleeding. In sponge form, gelatin adheres totissue and absorbs approximately forty-five times its own weight influids. Gelatin is typically absorbed within three to five weeks afterimplantation into the body.

Collagen is a bioabsorbable material, typically obtained from aprocessed animal source such as bovine corium (hide), bovine tendon, orporcine skin. Reprocessed insoluble collagen from animal sources iscommercially available in the form of sponges or non-woven webs. Thecollagen can formed into a structure of suitable size and shape toocclude the hollow anatomical structure, for example, a plug.Sponge-like porous plugs with pore diameters greater than 50 microns arepreferred for promoting cellular ingrowth. A dry, highly compressedcollagen plug when fully hydrated expands to several times itscompressed size within a short period of time upon contact with a bodilyfluid, tightly affixing itself to a particular location within a bloodvessel. Preferred collagen materials are marketed as COLLASTAT®Hemostatic Sponge (Vitaphore Corp.), VITACOL™ (Vitaphore Corp.), andSemex Collagen Powder (Semex Medical, Inc.). The collagen can becrosslinked with formaldehyde, glutaraldehyde, or other suitable agentsto increase the strength or compression modulus of the material and toslow its bioerosion in vivo. Particularly preferred collagen plugs aredisclosed in U.S. Pat. No. 5,456,693 to Conston, et al., the contents ofwhich are hereby incorporated by reference in their entirety.

Polyglycolic acid (PGA) is a synthetic absorbable polymer. Polyglycolicacid, which exhibits hydrolytic susceptibility, is typically absorbedwithin a few months post-implantation. Polylactide (PLA) is preparedfrom the cyclic diester of lactic acid (lactide) by ring openingpolymerization for high molecular weight polymers or by directcondensation for low molecular weight polymers. Lactic acid exists astwo optical isomers or enantiomers. The L-enantiomer occurs in nature,and a D,L racemic mixture results from the synthetic preparation oflactic acid. The time required for poly-L-lactide to be absorbed by thebody is relatively long compared to other bioabsorbable materials. Foamsmade from bioresorbable PLAs and/or PGAs are particularly preferred.

Polydioxanone can be suitable for use in preferred embodiments, as canpolycaprolactone, which is absorbed very slowly in vivo.

Poly-b-hydroxybutyrate is a biodegradable polymer that occurs in natureand can easily be synthesized in vitro. Poly-b-hydroxybutyrate is alsomelt processable. Copolymers of hydroxybutyrate and hydroxyvalerateexhibit more rapid degradation than does pure poly-b-hydroxybutyrate.

Synthetic absorbable polyesters containing glycolate ester linkages aresuitable for use as substrates in preferred embodiments. Similarcopolymers prepared using dioxanone instead of glycolide can also beemployed, as can poly(amino acids).

A bioabsorbable material suitable for use in preferred embodiments ismarketed under the tradename ATRIGEL® by Atrix Laboratories. ATRIGEL®consists of biodegradable polymers dissolved in biocompatible carriers,specifically, polylactic acid dissolved in N-methyl-2-pyrrolidonesolvent. Pharmaceuticals can be blended into ATRIGEL® at the time ofmanufacturing or can be added later by the physician at the time of use.When the liquid product is injected or placed in accessible tissue sitesthrough a cannula, displacement of the carrier with water in the tissuefluids causes the polymer to precipitate to form a solid film orimplant. Any drug or other substance (e.g., a sclerosant) encapsulatedwithin the implant is then released in a controlled manner as thepolymer matrix biodegrades with time. Depending upon the patient'smedical needs, the ATRIGEL® system can deliver small molecules,peptides, proteins, or other substances over a period ranging from daysto months.

Catgut, siliconized catgut, and chromic catgut are suitable for use incertain embodiments. Other naturally occurring materials include, butare not limited to, starches, cellulose, acetates, and thrombin.Selected natural materials can provoke a heightened inflammatoryresponse, which can be desirable for facilitating the occlusion process.However, synthetic materials are generally preferred over naturalmaterials for occluding the hollow anatomical structure due to theirgenerally predictable performance.

While bioabsorbable occluding materials are generally preferred, incertain embodiments biocompatible materials that are not alsobioabsorbable or biodegradable can be employed. For example, medicalgrade polyurethane sponges or foams such as HYPOL™ (The Dow ChemicalCo.), can be employed. Such urethane foams have good memorycharacteristics and a higher compression modulus in water than acollagen sponge of similar solids content. The polyurethane plugs can beemployed without modification, or can be impregnated with collagen orcrosslinked collagen.

2-Cyanoacrylic esters, more commonly referred to as cyanoacrylates, aresuitable for use in certain embodiments for occluding a hollowanatomical structure. Cyanoacrylates are hard glass resins that exhibitexcellent adhesion to high energy surfaces, such as tissue. Theexcellent adhesive properties of cyanoacrylate polymers arises from theelectron-withdrawing characteristics of the groups adjacent to thepolymerizable double bond, which accounts for both the extremely highreactivity or cure rate, and their polar nature, which enables thepolymers to adhere tenaciously to many diverse substrates. The abilityof cyanoacrylates to rapidly cure and bond to skin makes themparticularly well suited for use as medical adhesives. Cyanoacrylateadhesives suitable for use as medical adhesives include octyl2-cyanoacrylate marketed as DERMABOND™ topical skin adhesive by Ethicon,Inc., a Johnson & Johnson Company, of Somerville, N.J., and butylcyanoacrylate marketed as VETBOND™ by World Precision Instruments, Inc.of Sarasota, Fla.

Cyanoacrylate adhesives for medical and veterinary use generally includethe longer alkyl chain cyanoacrylates, including the butyl and octylesters. Octyl cyanoacrylates are the most widely used cyanoacrylateadhesive for tissue sealing. When bonding to tissue, octylcyanoacrylates are four times stronger and less toxic than butylcyanoacrylate. However, butyl cyanoacrylate is sometimes preferred forsealing deeper lacerations because it breaks down more easily and can beabsorbed by the tissue more quickly than octyl cyanoacrylate.Cyanoacrylate liquid monomers polymerize nearly instantaneously via ananionic mechanism when brought into contact with any weakly basic oralkali surface. Even the presence of a weakly basic substance such asmoisture is adequate to initiate the curing reaction. The curingreaction proceeds until all available monomer has reacted or until it isterminated by an acidic species. The time of fixture for cyanoacrylateoccurs within several seconds on strongly catalytic surfaces to severalminutes on noncatalytic surfaces. Surface accelerators or additivesenhancing the curing rate may be used to decrease the time of fixture onnoncatalytic surfaces. The cyanoacrylate adhesive can be formulated intoa bioerodable material by inclusion of a pore forming agent (e.g., anagent that is soluble in tissue fluids, and that dissolves to leavepores and fissures in the polymerized mass).

Other suitable adhesives can include epoxies, UV-activated adhesives,and heat-activated adhesives, as are known in the art. Suitablebiocompatible materials for use as occluding devices or materials, or inthe preparation of occluding devices, can include polysilicones,polyurethanes, and the like.

In certain embodiments, it can be preferred to employ a hydrogel as anoccluding material. Hydrogels form a specific class of polymericbiomaterials, and are generally defined as two- or multicomponentsystems consisting of a three-dimensional network of polymer chains andwater that fills the space between macromolecules. Depending on theproperties of the polymer or polymers used, as well as on the nature anddensity of the network joints, such structures in an equilibrium cancontain various amounts of water; typically in the swollen state themass fraction of water in a hydrogel is much higher than the massfraction of polymer. Two general classes of hydrogels can be defined:physical gels (pseudogels), where the chains are connected byelectrostatic forces, hydrogen bonds, hydrophobic interactions or chainentanglements (such gels are non-permanent and usually they can beconverted to polymer solutions by heating); and chemical (true,permanent) hydrogels with covalent bonds linking the chains.

The polymers used as hydrogels in the preferred embodiments preferablyexhibit at least moderate hydrophilic character. In practice, to achievehigh degrees of swelling, it is common to use synthetic polymers thatare water-soluble when in non-crosslinked form. Typical simple materialsemployed as hydrogels include but are not limited to poly(ethyleneoxide), poly(vinyl alcohol), polyvinylpyrrolidone, and poly(hydroxyethylmethacrylate). There are also natural polymers, such as polysaccharides,that can form hydrogels. Hydrogels commonly employed in soft contactlenses, wound dressings, drug-delivery systems, and the like, can besuitable for use in preferred embodiments. Hydrogels typically exhibitgood biocompatibility in the contact with blood, body fluids, andtissues. Hydrogels can be employed that are capable of reacting tovarious environmental stimuli as temperature, pH, ionic strength, soluteconcentration, electric field, light, sound, and the like. Hydrogelssuitable for use in preferred embodiments include cyclodextrins such asthose described in U.S. Publ. No. 2002/0019369 A1 to Li, et al., thecontents of which are hereby incorporated by reference in theirentirety.

Hydrogels can be employed in any suitable shape or form, e.g.,injectable liquid, or rod, plug, or other solid shape. A hydrogel in theform of a suitably sized swellable rod is particularly preferred for usein forming an occlusion in a hollow anatomical structure.

Additional Components in Bioabsorbable Material

In a preferred embodiment, the occluding device or occluding materialincorporates additional components. Such components can includephysiologically active materials, including but not limited totherapeutic agents, analgesic agents, anti-infectives, preservatives,binders, fillers, excipients, sclerosants, venoconstrictors, and thelike. In a particularly preferred embodiment, the occluding device oroccluding material is coated with a sclerosant, a venoconstrictor, orboth a sclerosant and a venoconstrictor. In other embodiments, theoccluding device or occluding material is coated with a tissue adhesive,optionally combined with a sclerosant, a venoconstrictor, or both asclerosant and a venoconstrictor. While it is generally preferred toincorporate sclerosants, venoconstrictors, or tissue adhesives ascoatings on the occluding device or occluding material, in otherembodiments such additional components can be mixed or blended with theoccluding material.

Sclerosants

In a preferred embodiment, a sclerosant is employed with the methods andmaterials for occluding hollow anatomical structures as describedherein. Sclerosants can include those conventionally employed insclerotherapy to close veins. Detergent sclerosants work by a mechanismknown as protein theft denaturation, in which an aggregation ofdetergent molecules forms a lipid bilayer in the form of a sheet, acylinder, or a micelle, which then disrupts the cell surface membraneand removes proteins from the cell membrane surface. The loss of proteincauses a delayed cell death. Unlike many other agents, the detergentsclerosants do not cause hemolysis, nor do they provoke directintravascular coagulation. Sodium morrhuate is a detergent sclerosantmade up of a mixture of saturated and unsaturated fatty acids extractedfrom cod liver oil. It is a biological extract rather than a syntheticpreparation, and the composition can vary from lot to lot, and asignificant fraction of its fatty acids and alcohols are of chainlengths that probably do not contribute to its effectiveness as asclerosant. It is unstable in solution, causes extensive cutaneousnecrosis if extravasated, and has been responsible for many cases ofanaphylaxis. Ethanolamine oleate, a synthetic preparation of oleic acidand ethanolamine, has weak detergent properties because its attenuatedhydrophobic chain lengths make it excessively soluble and decrease itsability to denature cell surface proteins. High concentrations of thedrug are necessary for effective sclerosis, and its effectiveness inesophageal varices depends upon mural necrosis. Allergic reactions areuncommon, but there have been reports of pneumonitis, pleural effusions,and other pulmonary symptoms following the injection of ethanolamineoleate into esophageal varices. It has a high viscosity that makesinjection difficult, a tendency to cause red cell hemolysis andhemoglobinuria, the occasional production of renal failure at highdoses, the possibility of pulmonary complications, and a relative lackof strength compared with other available sclerosants. Sodium tetradecylsulfate is a synthetic long chain fatty acid that is sold for medicaluse as a solution of up to 3% concentration with 2% benzoyl alcohol usedas a stabilizer. It is effective as a venous sclerosing agent inconcentrations from 0.1% to 3%, and has proven to be a reliable, safe,and effective sclerosant. The principal clinical problems with the drugare a tendency to cause hyperpigmentation in up to 30% of patients, asignificant incidence of epidermal necrosis upon extravasation, andoccasional cases of anaphylaxis.

Polidocanol (hydroxy-polyethoxy-dodecane) is a synthetic long-chainfatty alcohol employed as a sclerosant. Polidocanol is painless uponinjection. It does not produce necrosis if injected intradermally, andhas been reported to have a very low incidence of allergic reactions.Occasional anaphylactic reactions have been reported. In some patientsit may produce hyperpigmentation, although to a lesser extent than manyother agents. Telangiectatic matting after sclerotherapy withpolidocanol is as common as with any other agent. Scleremo, a compoundof 72% chromated glycerin, is a polyalcohol that is a very weaksclerosant and is principally useful in the sclerosis of small vessels.Its principal advantage is that it rarely causes hyperpigmentation ortelangiectatic matting, and that it very rarely causes extravasationnecrosis. The main problems with scleremo are that it is hard to workwith because it is extremely viscous, that it can be quite painful oninjection, that the chromate moiety is highly allergenic, and that ithas occasionally been reported to cause urethral colic and hematuria.

Strong solutions of hypertonic saline and other salt solutions are partof a class of solutions that are often referred to as osmoticsclerosants. These solutions have long been regarded as causingendothelial death by osmotic cellular dehydration. Hypertonic solutionsof saline as agents for sclerotherapy can be prepared as 20% or 23.4%solutions. The principal advantage of saline is the fact that it is anaturally occurring bodily substance with no molecular toxicity. Becauseof effects of dilution, it is difficult to achieve adequate sclerosis oflarge vessels without exceeding a tolerable salt load. It can causesignificant pain on injection, and significant cramping after atreatment session. If extravasated, it almost invariably causessignificant necrosis. Because it causes immediate red blood cellhemolysis and rapidly disrupts vascular endothelial continuity, it isprone to cause marked hemosiderin staining that is not very cosmeticallyacceptable. Sclerodex is a mixture of 25% dextrose and 10% sodiumchloride, with a small quantity of phenethyl alcohol. A primarilyhypertonic agent, its effects are similar to those of pure hypertonicsaline, but the reduced salt load offers certain benefits. Like purehypertonic saline, it is somewhat painful on injection, and epidermalnecrosis continues to be the rule whenever extravasation occurs.Polyiodinated iodine is a mixture of elemental iodine with sodiumiodide, along with a small amount of benzyl alcohol. It is rapidlyionized and rapidly protein-bound when injected and most likely works bylocalized ionic disruption of cell surface proteins in situ. In vivoconversion of ionized iodine to iodide renders the solution ineffectiveas a sclerosant, thus localizing the sclerosing effects to the immediatearea of injection. It has a high tendency to cause extravasationnecrosis, its limited effectiveness at a distance from the injectionsite, and the risks of anaphylaxis and of renal toxicity that areassociated with ionic iodinated solutions.

Other chemical sclerosants exist that act by a direct or indirectchemical toxicity to endothelial cells: by poisoning some aspect ofcellular activity that is necessary for endothelial cell survival. Suchagents are less useful to the extent that they also poison other bodilycells. They also lack another of the key attributes of a goodsclerosant: they remain toxic to some degree even after extremedilution, so that there is no real threshold below which injury will notoccur.

In a preferred embodiment, occlusion of a hollow anatomical structure ateither end is achieved as described above, and the open space in betweenthe occlusions is filled with a sclerosant. This occlusion method isparticularly preferred for occluding varicose veins.

In certain embodiments it is preferred to inject a sclerosant directlyinto the hollow anatomical structure. However, in certain embodiments itcan be desired to apply sclerosant by placing a sponge or fibrous massto which sclerosant has been applied in the hollow anatomical structure.

Venoconstrictors

In a preferred embodiment, a venoconstrictor is employed with themethods and materials for occluding hollow anatomical structures asdescribed herein. Venoconstrictors include, but are not limited tosodium, potassium, epinephrin, norepinephrine, phenylephrine,vasopressin, noradrenaline, and the like.

In a preferred embodiment, a venoconstrictor is combined with thebioabsorbable material, or is applied or administered separately fromthe bioabsorbable material. For example, the venoconstrictor can beinjected first, endovenously, then the bioabsorbable material can beinjected endovenously. Alternatively, the venoconstrictor can beinjected first, perivenously, then the bioabsorbable material can beinjected endovenously.

The venoconstrictor reduces the volume of the vein, such that lessmaterial is required to occlude the vein. The vein can be easier tofill, and better adhesion of the bioabsorbable occlusive agent, ortissue adhesive, is observed. Sodium-potassium mixtures are particularlypreferred venoconstrictors. However, any suitable venoconstrictor can beemployed.

Medicaments and Other Auxiliary Substances

Any suitable physiologically active substance or excipient can beemployed in connection with the occluding devices or materials ofpreferred embodiments. Preferred substances include, but are not limitedto, anti-inflammatory agents, anti-infective agents, anesthetics,pro-inflammatory agents, preservatives, cell proliferative agents,tretinoin, procoagulants, fillers, binders, surfactants, and the like.

Suitable anti-inflammatory agents include but are not limited to, forexample, nonsteroidal anti-inflammatory drugs (NSAIDs) such aspirin,celecoxib, choline magnesium trisalicylate, diclofenac potassium,diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen,ibuprofen, indomethacin, ketoprofen, ketorolac, melenamic acid,nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib,salsalate, sulindac, and tohnetin; and corticosteroids such ascortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone,betamethesone, beclomethasone dipropionate, budesonide, dexamethasonesodium phosphate, flunisolide, fluticasone propionate, triamcinoloneacetonide, betamethasone, fluocinolone, fluocinonide, betamethasonedipropionate, betamethasone valerate, desonide, desoximetasone,fluocinolone, triamcinolone, triamcinolone acetonide, clobetasolpropionate, dexamethasone, silver, silver complexes, and silver salts.

Anti-infective agents may include, but are not limited to, anthelmintics(mebendazole), antibiotics including aminoclycosides (gentamicin,neomycin, tobramycin), antifingal antibiotics (amnphotericin b,fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin,micatin, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime,ceftazidime, ceftriaxone, cefuroxime, cephalexin), beta-lactamantibiotics (cefotetan, meropenem), chloramphenicol, macrolides(azithromycin, clarithromycin, erythromycin), penicillins (penicillin Gsodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin,piperacillin, ticarcillin, benzylpenicillin), tetracyclines(doxycycline, minocycline, tetracycline), bacitracin; rifampicin;lincomycin; clindamycin; colistimethate sodium; polymyxin b sulfate;vancomycin; antivirals including acyclovir, amantadine, didanosine,efavirenz, foscamet, ganciclovir, indinavir, lamivudine, nelfinavir,ritonavir, saquinavir, stavudine, valacyclovir, valganciclovir,zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamides(sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone;metronidazole; pentamidine; sulfanilamidum crystallinum; gatifloxacin;and sulfamethoxazole/trimethoprim. Anti-infective agents such as silver,silver ions, colloidal silver, silver sulfadiazine, and silver nitratecan also be employed.

Anesthetics may include, but are not limited to ethanol, bupivacaine,chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine,ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol,sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine,methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol,nalbuphine, tramadol, benzocaine, dibucaine, ethyl chloride, xylocaine,and phenazopyridine.

Other substances that can be incorporated into occluding materials oroccluding devices of preferred embodiments include variouspharmacological agents, excipients, sclerosants, venoconstrictors, andother substances well known in the art of pharmaceutical formulations.Other substances include, but are not limited to, antiplatelet agents,anticoagulants, coagulants, ACE inhibitors, cytotoxic agents, ionic andnonionic surfactants (e.g., PLURONIC™, TRITON™), detergents (e.g.,polyoxyl stearate, sodium lauryl sulfate), emulsifiers, demulsifiers,stabilizers, aqueous and oleaginous carriers (e.g., white petrolatum,isopropyl myristate, lanolin, lanolin alcohols, mineral oil, sorbitanmonooleate, propylene glycol, cetylstearyl alcohol), solvents,preservatives (e.g., methylparaben, propylparaben, benzyl alcohol,ethylene diamine tetraacetate salts), thickeners (e.g., pullulin,xanthan, polyvinylpyrrolidone, carboxymethylcellulose), plasticizers(e.g., glycerol, polyethylene glycol), antioxidants (e.g., vitamin E),buffering agents, and the like.

The auxiliary substances can be employed in connection with theoccluding device or material in any suitable manner. For example, one ormore auxiliary substances can be mixed directly into an occludingmaterial, coated on or otherwise applied to an occluding device,impregnated into an occluding device, placed in a hollow anatomicalstructure prior to placement of the occluding device or material,applied to a portion of the hollow anatomical structure after placementof the occluding device or material, or any combination thereof.Different auxiliary substances can be employed in different manners.Likewise, a single auxiliary substance can be employed in differentmanners, or different auxiliary substances can all be employed in thesame manner.

In preferred embodiments, auxiliary substances can be incorporated intothe occluding material or occluding device in encapsulated form. Certainsubstances may contain reactive groups that prematurely initiate curingof an uncured bioabsorbable material. Other substances may be sensitiveto the components of the occluding material and as a result may undergoadverse chemical reactions or become less active or nonactive.Alternatively, controlled or delayed release of the agent from anoccluding material may be desired. Microencapsulation is an effectivetechnique to avoid undesired chemical interaction between auxiliarysubstances and occluding materials, and to provide controlled release ofauxiliary substances from an occluding material.

In a preferred embodiment, the auxiliary substances are entrapped intohydrophilic gelatin microcapsules and mixed with the uncured or fluidoccluding material. However, any suitable material can be employed forthe microcapsule. Typical encapsulating materials include, but are notlimited to, gum arabic, gelatin, ethylcellulose, polyurea, polyamide,aminoplasts, maltodextrins, and hydrogenated vegetable oil. Particularlypreferred encapsulating materials include, but are not limited to, gumarabic, gelatin, diethylcellulose, maltodextrins, and hydrogenatedvegetable oils. Gelatin is particularly preferred because of its lowcost, biocompatibility, and the ease with which gelatin shellmicrocapsules may be prepared. In certain embodiments, however, othershell materials may be preferred. The optimum shell material may dependupon the particle size and particle size distribution of the fillingmaterial, the shape of the filling material particles, compatibilitywith the filling material, stability of the filling material, and therate of release of the filling material from the microcapsule.

Microencapsulation techniques typically involve the coating of smallsolid particles, liquid droplets, or gas bubbles with a thin film of amaterial, the material providing a protective shell for the contents ofthe microcapsule. Microcapsules suitable for use in the preferredembodiments may be of any suitable size, typically from about 1 μm orless to about 1000 μm or more, preferably from about 2 μm to about 50,60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, or 900 μm, andmore preferably from about 3, 4, 5, 6, 7, 8, or 9 μm to about 10, 15,20, 25, 30, 35, 40 or 45 μm. In certain embodiments, it may be preferredto use nanometer-sized microcapsules. Such microcapsules may range fromabout 10 nm or less up to less than about 1000 nm (1 μm), preferablyfrom about 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, or 90 nm upto about 100, 200, 300, 400, 500, 600, 700, 800, or 900 nm. While inmost embodiments a solid phase substance is encapsulated, in certainembodiments it may be preferred to incorporate a liquid or gaseoussubstance. Liquid or gas containing microcapsules can be prepared usingconventional methods well known in the art of microcapsule formation,and such microcapsules may be incorporated into the adhesives of thepreferred embodiments. In certain embodiments, it may be preferred thatthe microcapsules contain a plurality of substances, e.g., a pluralityof medicaments, or a plurality of substances not including medicamentsor pharmaceutical formulations.

The occluding materials or occluding devices of preferred embodimentsare preferably sterile. The occluding materials can contain any desiredsubstances, including auxiliary substances such as are described instandard texts, such as “Remington: The Science and Practice ofPharmacy”, Lippincott Williams & Wilkins; 20th edition (Jun. 1, 2003)and “Remington's Pharmaceutical Sciences,” Mack Pub. Co.; 18^(th) and19^(th) editions (December 1985, and June 1990, respectively),incorporated herein by reference in their entirety.

Controlled release formulations can be employed wherein the auxiliarysubstances are incorporated into an occluding material that permitsrelease by, e.g., diffusion or leaching mechanisms. Slowly degeneratingsubstances can also be incorporated into the occluding material so as tofacilitate bioabsorption or bioerosion. Other delivery systems caninclude timed release, delayed release, or sustained release deliverysystems for one or more components of the occluding material. It isgenerally preferred that a material is released over a period of fromabout an hour or less to about a month or more, more preferably over aperiod of from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, or 24 hours to about 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, or 30 days.

Solvents

In certain embodiments, it can be desirable to use a solvent orpenetration enhancer, e.g., dimethyl sulfoxide (DMSO), ethanol, oleicacid, propylene glycol, or the like, in connection with the occludingmaterial or one or more of any additional components present. Forexample, the solvent or penetration enhancer can be mixed with anoccluding material or a sclerosant to enhance adsorption or uptake ofthe material or sclerosant by the adjacent tissue. If the occludingdevice is a sponge or some other porous form, the device can be soakedin or permeated by the solvent or penetration enhancer (either in pureform or diluted by a suitable solvent).

General Methodology

The general methodology employed to occlude a hollow anatomicalstructure typically involves identifying a site to be occluded, andplacing an occluding device or occluding material at the site. In apreferred method, the site at which the occluding device or material isplaced is identified by any suitable method. Suitable methods include,but are not limited to, ultrasound, compression, endoscopy, fluoroscopy,other methods utilizing contrast media, and the like. Once the placementsite is identified, the occluding device or material is placed orinserted either within or external to the hollow anatomical structure.Placement can be achieved using any suitable device, including but notlimited to a needle, a catheter, guide wire, a trocar, otherintravascular delivery devices, cannula, and the like. Placement methodsinclude but are not limited to insertion, manual injection, controlledfeed, controlled pull, delivery through a sheath, or delivery throughany other suitable tubular or hollow member, pneumatic, electrical, andthe like.

Generally, the desired site within a hollow anatomical structure, suchas a blood vessel, is accessed with a catheter. For small diametertorturous vessels, the catheter can be guided to the site by the use ofa guide wire. Once the site has been reached, the catheter lumen iscleared by removing the guide wire. An occluding material can then beinserted through the catheter and cured or solidified in situ. Forplacement of plugs or other solid occluding materials, the material canbe loaded by a pusher wire. The material can be attached to the end ofthe pusher wire via a cleavable joint (e.g., a joint that is severableby heat, electrolysis, electrodynamic activation, or the like) or amechanical joint that permits the material to be detached from thedistal end of the pusher wire by mechanical manipulation. Alternatively,the material can be free and detached from the pusher wire, and simplypushed through the catheter and expelled from the distal end of thecatheter at the desired location. Also, the material or device can beexposed and placed through removing an outer sheath.

If the occluding device is preformed, it can immediately occlude thevessel upon placement. In certain embodiments, wherein the occludingdevice is a sponge or other expanding material, the device absorbs fluidso as to expand and block the hollow anatomical structure.Alternatively, the occluding device can be cured, solidified, or formedin situ. For example, an occluding material is injected into a hollowanatomical structure and cured or solidified in place, the solidifiedmaterial forming an occluding device.

In a particularly preferred embodiment, a bioabsorbable material isinjected into a hollow anatomical structure to occlude the hollowanatomical structure. As the material absorbs fluid and is replaced byfibrous tissue, the hollow anatomical structure is permanently closedusing the body's natural healing response. While bioabsorbable materialsare particularly preferred, in certain embodiments it can be preferredto employ a biocompatible material that is not bioabsorbable, or toemploy a bioerodable material (for example, a material that becomescomminuted upon exposure to physiological conditions).

Occlusion of the Hollow Anatomical Structure

Occlusion of the hollow anatomical structure can be achieved by variousmechanisms, and can be permanent or temporary. For example, theocclusion can be achieved by permanent or temporary blockage of thehollow anatomical structure by the occluding device, which acts as abarrier to flow of fluid (e.g., gas, liquid) through the hollowanatomical structure. Alternatively, the occluding device can form atemporary (e.g., biodegradable) or permanent scaffold for growth oftissue, wherein the tissue ultimately forms the occlusion. Similarly,the occluding device can induce formation of an organized thrombus.

In an alternative embodiment, occlusion of the hollow anatomicalstructure is achieved by using, e.g., tissue adhesives which adhereopposing walls to each other in order to collapse the hollow anatomicalstructure and eventually result in permanent occlusion of the hollowanatomical structure, e.g., by the formation of scar tissue. Occlusionof the hollow anatomical structure by adhering opposing walls togetheris preferably achieved by injecting a tissue adhesive into the hollowanatomical structure, then applying compression or a vacuum to collapsethe hollow anatomical structure, causing the walls to contact andadhere. Alternatively, compression or vacuum, or another method can beemployed to collapse the hollow anatomical structure. After the hollowanatomical structure is collapsed, an adhesive is injected into thecollapsed hollow anatomical structure, the adhesive adhering thecollapsed walls to each other. Once adhesion is achieved, then thevacuum, compression, or other force collapsing the hollow anatomicalstructure is removed, and the walls remain adhered to each other. Analternative method for collapsing the hollow anatomical structureutilizes a spreader. The spreader is placed into the hollow anatomicalstructure to force the sides of the vessel outward to collapse, therebycoapting (i.e., placing in close proximity or contact or cause to adhereby physical proximity or conglutination) the walls of the hollowanatomical structure to improve proximity and reduce interior space inorder to improve durability or quality of the occlusion. Application ofexternal linear compression on the outside of the hollow anatomicalstructure can also be employed to collapse or coapt the walls. Inpreferred embodiments, compression of the hollow anatomical structure isemployed in conjunction with use of an adhesive to achieve occlusion.However, in other embodiments it can be preferred to use compressionalone, or adhesive alone.

Occlusion of the hollow anatomical structure can be contiguous ornon-contiguous. In contiguous occlusion, all, or substantially all, ofthe volume to be occluded is filled with an occluding device ormaterial, or sealed with a tissue adhesive. In non-contiguous occlusion,only a portion of the volume to be occluded is filled with an occludingdevice or material. For example, one end of a hollow anatomicalstructure can be occluded with an occluding device or material, such asa bioabsorbable material. By sealing one end of the hollow anatomicalstructure, the volume behind the occluding device or material iseffectively blocked to fluid flow. Alternatively, both ends of a hollowanatomical structure can be sealed with an occluding device or material,and the volume between the ends left open. In these embodiments, theoccluding device or material is preferably a bioabsorbable material.However, a tissue adhesive can also be employed to occlude one end of ahollow anatomical structure, or both ends of a hollow anatomicalstructure, leaving the middle open. Over time this open section can beoccluded by the body's healing response.

When the hollow anatomical structure possesses a valve, an occludingmaterial or tissue adhesive can be applied on or around valve to closethe valve off and prevent flow through it. A second or third occludingdevice or material can be employed on one or both sides of the valve tocontain in place the material or adhesive applied on or around thevalve. Alternatively, one or two separate occluding devices can beemployed to contain a material in a hollow anatomical structure betweenthe occluding devices. These occluding devices can form temporaryocclusions or permanent occlusions. For example, an occluding device canbe employed to seal one end (or two occluding devices can be employed toseal two ends) of a hollow anatomical structure such that a temporaryvacuum in the hollow anatomical structure can be formed to aid incollapsing or coapting the hollow anatomical structure, or to aid inreducing the volume of the hollow anatomical structure. A tissue sealantcan then be injected into the collapsed space to seal the wallstogether. Once the walls are sealed together, the occluding device canbe removed or left in place. Alternatively, a temporary occluding devicecan block a hollow anatomical structure, and a bioabsorbable material inliquid form can be injected against the temporary occluding device andpermitted to cure or solidify in place. Once the bioabsorbable materialhas cured or solidified, the temporary occluding device can be removed.

As discussed above, bioabsorbable materials are particularly preferredfor use in forming occlusions in hollow anatomical structures. Thebioabsorbable material provokes a fibrotic response, whereby thebioabsorbable material is replaced as tissue builds up, whereby thetissue forms an occlusion. Preferably, the bioabsorbable material can beinserted into the hollow anatomical structure by injection. Thebioabsorbable material can be placed by a single injection into, orsurrounding, the hollow anatomical structure to be occluded.Alternatively, multiple injections can be employed, either at the samesite, or at a series of different sites, at the same time, or atdifferent times.

Methods employing multiple injections of bioabsorbable materials canoffer certain benefits. For example, a small amount of material can beinjected, permitted to cure or solidify, then additional material can beadded to the same site in one or more additional injections, therebybuilding up a cured or solidified structure of bioabsorbable material inthe hollow anatomical structure. Alternative, a first material can beinjected at a site, and then a second, different material can beinjected at the same site or a different site. Additional injections ofthe same material, or one or more different materials, can then beconducted. When the bioabsorbable material cures or solidifies in place,it can be preferred to inject the uncured or fluid bioabsorbablematerial into the hollow anatomical structure, then inject a cureinitiator, catalyst, or accelerator into or adjacent to the material, tofacilitate formation of a cured or solidified bioabsorbable material.Alternatively, the cure initiator, catalyst, or accelerator can beinjected first, then the prepolymer.

As discussed above, a variety of bioabsorbable materials can beemployed. Particularly preferred bioabsorbable materials expand afterplacement, facilitating effective occlusion of the hollowanatomical-structure. For example, a hydrogel can be employed thatabsorbs water or another fluid from the surrounding environment. Othermaterials can exhibit swelling or expansion upon exposure to heat (e.g.,body temperature), or to physiological conditions (e.g., pH).

In particularly preferred embodiments, an injectable bioabsorbable orbiocompatible material is employed that is sufficiently viscous or thickso as not to exhibit an undesired degree of migration from the site atwhich it is placed. An injectable bioabsorbable or biocompatiblematerial that exhibits adhesive properties is also particularlypreferred for migration prevention or inhibition.

Occlusion of the Hollow Anatomical Structure by Fibrotic TissueFormation

While it is generally preferred to achieve occlusion of the hollowanatomical structure by placing an occluding device or occludingmaterial in the hollow anatomical structure, occlusion can also beachieved by placing an occluding device or material in the perivenousspace. In a preferred embodiment, an occluding material is injected intothe perivenous space, or in a fascial compartment exterior to a vein.The occluding material can shrink upon curing or solidifying, or releasea venoconstrictor and/or sclerosant, thereby occluding the vein. In thisembodiment, migration of the occluding material can be avoided, sincethe material is not subjected to forces from fluid flowing through thehollow anatomical structure. Biocompatibility concerns can also bereduced, since the occluding material is not in contact with circulatingblood.

In certain preferred embodiments, blood collects and coagulates in,around, or near the occluding device or occluding material. A thrombusis formed and eventually fibrous tissue grows. In some techniques, agrowth factor can be used with the occluding device or occludingmaterial to promote fibrous tissue growth. In some embodiments, athrombin coating or seeding of the occluding device or occludingmaterial can promote better tissue ingrowth. There are many ways tostimulate tissue ingrowth in a biodegradable polymer. One method is tocreate a loose polymer scaffold and fill the interstitial space withhydrogel, e.g., fibrin gel. Fibrin gel induces tissue ingrowth. Tissuegrowth factor, e.g., fibroblast growth factor, can also be incorporatedinto the occluding device or occluding material with the hydrogel topromote tissue ingrowth. In this approach, the occluding device oroccluding material is delivered first, and then fibrinogen, thrombin,and/or growth factor solution is injected into the vein. The solutionfills in the interstitial space in the occluding device or occludingmaterial and polymerizes to form hydrogel, which serves as a matrix forrapid tissue ingrowth. An alternative approach to the fibrin gel is todirectly mix autogenous blood with thrombin and inject the mixed bloodinto the vein near the occluding device or occluding material. Thiscreates a blood clot-like structure to fill the space and the clotproperty can be controlled by thrombin concentration. An occludingdevice or occluding material comprising thrombin is effective ininducing tissue ingrowth and has advantages over natural clotting.According to another technique, a mix of autologous blood and fibrin isinjected just before the occluding device or occluding material isdeployed so that it contacts or penetrates the occluding device oroccluding material when it is introduced into the hollow anatomicalstructure.

Additionally, there are other modifications that can be made to theoccluding device or occluding material. The surface of the occludingdevice, as well as the occluding material itself, can be modified, e.g.,charge modified, chemically modified, porosified, or roughened to bepreferentially fibrinogen-philic or albumin-phobic. Within the first 1-3seconds after implantation of a hydrophobic device or material in theblood plasma stream, protein begins to adsorb on the surface. Just asimmediately, Factor XIIa is activated, starting the clotting cascade. Ifalbumin preferentially lays down on the device or material, it will tendto passivate the surface, rendering it less reactive. Thus, it isadvantageous to prevent or limit albumin adsorption and topreferentially adsorb fibrinogen onto the surface of the device ormaterial by adjusting the polymer, or surface of the polymer, chargingthe surface, or by otherwise increasing its hydrophobicity. In someembodiments, pre-adsorption of fibrinogen onto the device orincorporation of fibrinogen into the material promotes non-passivation.Fibrinogen adsorption causes blood to not see the implant and thus helpsto prevent any endothelialization of the clot. In some embodiments,making surface modifications can improve fibrotic occlusion, with orwithout adding thrombin. By the intrinsic clotting cascade mechanism,thrombin acts on the fibrinogen (a reactive protein monomer circulatingin blood plasma, liquid) to become fibrin monomers, which are then crosslinked by Factor XIII to become fibrin (a solid). This cross linkedfibrin forms an organized thrombus (i.e., a fibrotic occlusion). Oneexample of a material capable of forming an occlusion by this type ofmechanism is rough-surfaced DACRON® DACRON® is a hydrophobic polyesterfiber comprising a condensation polymer obtained from ethylene glycoland terephthalic acid, which preferentially adsorbs fibrinogen overalbumin, quickly creating fibrin and thus mural (wall) thrombus, andhelping to prevent endothelialization. Silicones and polyurethanes donot activate the clotting cascade as aggressively because they bothpreferentially adsorb albumin over fibrinogen.

Other mechanisms that assist in the formation of fibrotic occlusionsinclude inhibiting the natural fibrinolytic system in the region of theoccluding device or occluding material. As mentioned earlier, FactorXIIa starts the clotting cascade, but it also converts plasminogen toplasmin. Plasmin is not desired because it is the enzyme that lysesthrombus. By inhibiting the conversion of plasminogen to plasmin, thenatural drive to lyse the desired thrombus in the region of the implantcan be prevented. Plasmin is similar to thrombin, except that thrombinonly cleaves fibrinogen to create fibrin monomers, which is desired forthrombus formation. In contrast, plasmin cleaves both fibrinogen andfibrin, creating fibrin split products (FSPs) or fibrin degradationproducts. These are normally removed, but if they are not, they reachhigh concentrations and become potent inhibitors of clot formation. FSPsinhibit cross linking of the fibrin monomers by preventing them fromcontacting each other and thereby creating a fibrotic occlusion. Tissueplasminogen activator (tPA) can be used for thrombolysis, as well asother drugs like ReoPro (a GPIIb/IIIa inhibitor that binds to humanplatelet IIb/IIIa receptors to prevent platelet aggregation). Drugs orsurface coatings, such as tissue plasminogen de-activator (tPDA), can beemployed to cause platelets to aggregate more aggressively and/orpromote aggressive prevention of activation of plasminogin in the regionof the occluding device or occluding material.

Kits for Initiating Occlusion of a Hollow Anatomical Structure

The bioabsorbable material and other components can be provided to anadministering physician or other health care professional in the form ofa kit. The kit is a package which houses a container which contains thebioabsorbable material in uncured or fluid form, or in the form of a twoor more component mixture that can be mixed to form a material thatshortly thereafter cures or solidifies in place after injection. The kitmay optionally also contain one or more other therapeutic agents. Thekit can optionally contain one or more diagnostic tools and instructionsfor use. For example, a kit can contain a bioabsorbable material, asdescribed herein, and directions for placing an occlusion. The kit cancontain suitable delivery devices, e.g., syringes, catheters, and thelike, along with instructions for placing the occlusion. The kit canoptionally contain instructions for storage, reconstitution (ifapplicable), preparation, and administration of any or all bioabsorbablematerials or other materials included in the kit. The kits can include aplurality of containers reflecting the number of occlusions to besituated in a subject.

Prevention of Migration of Occluding Device

To assist the occluding device in remaining in place after insertion, itcan be advantageous to employ certain materials or methods to yield amore stable occlusion. For example, the occluding device can include oneor more tissue adhesives. Venoconstrictors can be employed to reduce thevolume of the hollow anatomical structure, facilitating formation of aneffective occlusion. The hollow anatomical structure can be overfilledwith an occluding material, making a diameter of the treated segmentlarger than that of the distal hollow anatomical structures. Multipleinjections can be employed. For example, one material can be employed asan occluder for the length of a treated segment, and another materialcan be used in smaller amounts at one end of a treated segment toprevent migration. As an example, an adhesive, solid plug,venoconstrictor, or heat can be employed to occlude one or more ends ofa hollow anatomical structure, and a sclerotherapeutic agent or tissueadhesive can be injected into the length of the hollow anatomicalstructure between the occluded ends.

In a preferred embodiment, occlusion of the hollow anatomical structureis achieved using a tissue adhesive in conjunction with a short termvenoconstrictor administered before, during, or after insertion of thetissue adhesive in the hollow anatomical structure. The venoconstrictorproduces apposition of vein walls during the critical curing orsolidifying time of the adhesive, then the adhesive takes over tomaintain the walls in apposition when the chemical constriction causedby the venoconstrictor wears off. Similarly, an occluding deviceconsisting of a substance that shrinks upon application of heat, e.g.,collagen, with a tissue adhesive can be employed. After insertion, thecollagen is caused to shrink by application of heat, but the adhesivemaintains the constriction of the hollow anatomical structure aftershrinkage is completed.

Occlusion of a hollow anatomical structure can also be achieved by anexothermic reaction of bioerodable material. For example, cyanoacrylatebased adhesives generate heat when curing is initiated upon contact withmoisture in tissue. The heat generated during the process facilitatesocclusion of the hollow anatomical structure, e.g., by causing heatinduced tissue damage. Other systems can also be employed that generateheat, e.g., a two component system which generates heat when mixed. Thesystem can facilitate occlusion through generation of heat alone, or thesystem can perform other functions, e.g., tissue adhesion, chemicalinduced sclerosis, and the like.

In certain embodiments, hollow anatomical structure occlusion ispreferably attained by employing a bioabsorbable material wherein theviscosity of the material is adjustable. A low viscosity bioabsorbablematerial can facilitate delivery, especially to small diameter hollowanatomical structure, while a high viscosity bioabsorbable material canresist migration and effectively block blood flow. The viscosity of thebioabsorbable material can be time dependent (e.g., viscosity increaseswith passage of time), temperature dependent (e.g., becomes more or lessviscous upon application of heat or at body temperature, or curing isthermally initiated), moisture dependent (e.g., moisture acts as acatalyst to a curing reaction), chemical dependent (e.g., a chemicalacts as a curing agent), or photochemically dependent (e.g., light, suchas ultraviolet light, initiates curing).

Examples of Insertion of Bioabsorbable Material Using Catheter

Any suitable catheter can be employed for placing the bioabsorbablematerial in the hollow anatomical structure. Catheters include variousdesigns, including single and multiple lumen designs. In a preferredembodiment, a single lumen tube is employed wherein the bioabsorbablematerial is injected into the hollow anatomical structure through adistal leg of the catheter. Alternatively, a single lumen catheterincorporating side holes can be employed. In a preferred embodiment,bioabsorbable material is injected into the hollow anatomical structureat a point furthest away from the access site. The catheter is thenpulled back while injecting bioactive agent through the catheter (e.g.,paint style injection). Pull back injection techniques can be employedwith any suitable catheter design, including catheters with a distalleg, or catheters permitting side hole injection.

In certain embodiments, a needle can be employed in placing theoccluding material. Any suitable syringe can be employed, which utilizesa needle of suitable length and bore for the hollow anatomical structureto be occluded. Preferably, a needle of a length of about 1 inch or lessto about 5 inches or more is employed, more preferably, about 1.5 or 2inches to about 2.5, 3, 3.5, 4, or 4.5 inches. Preferably, the bore ofthe needle is from about 0.10″ or less to about 0.01″ or more. A largerbore can facilitate delivery of viscous occluding materials.

Use of catheters to deliver a polymer to the interior surface of atissue lumen is disclosed in U.S. Pat. No. 6,699,272 to Slepian, et al.the contents of which are hereby incorporated by reference in theirentirety.

Curable or Solidifiable Biodegradable Materials

In a particularly preferred embodiment, occlusion of a hollow anatomicalstructure is achieved using a biodegradable polymer which can beinserted into the hollow anatomical structure as a liquid via, forexample, a syringe and needle, but which solidifies or cures shortlyafter dosing to form a solid. Such biodegradable polymers are describedin U.S. Pat. No. 4,938,763 to Dunn, et al., the contents of which arehereby incorporated by reference in their entirety. Such polymers slowlybiodegrade within the body and allow natural tissue to grow and replacethe polymer as it disappears. One particularly preferred polymer ispoly(DL-lactide-co-glycolide).

In one embodiment, a biodegradable polymer is dissolved in abiocompatible solvent to form a liquid, which can then be inserted intothe hollow anatomical structure via a syringe and needle. As the solventmigrates from within the polymer matrix, the polymer cures orsolidifies, yielding a solid structure that occludes the hollowanatomical structure. Suitable biodegradable polymers includepolylactides, polyglycolides, polycaprolactones, polyanhydrides,polyamides, polyurethanes, polyesteramides, polyorthoesters,polydioxanones, polyacetals, polyketals, polycarbonates,polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates,polyhydroxyvalerates, polyhydroxyalkanoates (PHAs), polyalkyleneoxalates, polyalkylene succinates, poly(malic acid), poly(amino acids),polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin,chitosan, and copolymers, terpolymers, or combinations or mixtures ofthese materials. It is preferred that the biodegradable polymer benontoxic. However, in certain embodiments it can be desirable for thepolymer to exhibit some degree of cytotoxicity, which facilitates theocclusion process. It is preferred that the solvent for thebiodegradable polymer be nontoxic, water miscible, and otherwisebiocompatible. Cytotoxic solvents can be preferred in certainembodiments for facilitating occlusion. Examples of suitable solventsinclude N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propyleneglycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone,dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam,decylmethylsulfoxide, oleic acid, and 1-dodecylazacycloheptan-2-one.

In an alternative embodiment, a thermosetting functionalizedbiodegradable or bioabsorbable polymer system is inserted into thehollow anatomical structure, then crosslinked in place. Thethermosetting system can comprise a reactive, liquid, oligomeric polymeror polymers which cure or solidify in place, typically with the additionof a curing catalyst. The biodegradable polymers previously describedcan be employed in thermoplastic systems, after addition of functionalgroups on the ends of the prepolymer which can be reacted with acryloylchloride to produce acrylic ester capped prepolymers. Alternatively, thebiodegradable polymer can be functionalized with other suitable systemsto yield a thermosetting polymer system.

All references cited herein are incorporated herein by reference intheir entirety. To the extent publications and patents or patentapplications incorporated by reference contradict the disclosurecontained in the specification, the specification is intended tosupersede and/or take precedence over any such contradictory material.

The term “comprising” as used herein is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forthherein are approximations that may vary depending upon the desiredproperties sought to be obtained. At the very least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of any claims in any application claiming priority to the presentapplication, each numerical parameter should be construed in light ofthe number of significant digits and ordinary rounding approaches.

The above description discloses several methods and materials of thepresent invention. This invention is susceptible to modifications in themethods and materials, as well as alterations in the fabrication methodsand equipment. Such modifications will become apparent to those skilledin the art from a consideration of this disclosure or practice of theinvention disclosed herein. Consequently, it is not intended that thisinvention be limited to the specific embodiments disclosed herein, butthat it cover all modifications and alternatives coming within the truescope and spirit of the invention.

1. Apparatus for occluding a hollow anatomical structure in a patient,the apparatus comprising: a bioresorbable material; wherein, uponplacement in a hollow anatomical structure, the material blocks fluidflow through the hollow anatomical structure to a degree sufficient toinduce a durable occlusion of the hollow anatomical structure.
 2. Theapparatus of claim 1, wherein the hollow anatomical structure is a bloodvessel.
 3. The apparatus of claim 1, wherein the material comprises aviscous flow-blocking material.
 4. The apparatus of claim 1, wherein thematerial is configured to be injectable.
 5. The apparatus of claim 4,wherein the material is configured to be sufficiently viscous tomaintain its position in a hollow anatomical structure with an insidediameter greater than or equal to about 2 mm.
 6. The apparatus of claim5, wherein the hollow anatomical structure comprises a blood vessel. 7.The apparatus of claim 4, wherein the material is configured to besufficiently flowable to flow into a hollow anatomical structure with aninside diameter less than or equal to about 2 mm.
 8. The apparatus ofclaim 7, wherein the hollow anatomical structure comprises a bloodvessel.
 9. The apparatus of claim 4, wherein the material is selectedfrom the group consisting of collagen, fibrinogen, fibronectin,vitronectin, laminin, thrombin, gelatin, and mixtures thereof, so as tosubstantially block flow into the hollow anatomical structure by causingclotting and fibrotic tissue occlusion.
 10. The apparatus of claim 4,wherein the material is curable in situ upon placement in the hollowanatomical structure.
 11. The apparatus of claim 4, wherein the materialis configured to undergo a viscosity change in situ after placement inthe hollow anatomical structure.
 12. The apparatus of claim 11, whereinthe viscosity change is manifested by at least one process selected fromthe group consisting of crosslinking, curing, hardening, thickening, andswelling.
 13. The apparatus of claim 1, wherein the material is in aform of a sponge.
 14. The apparatus of claim 13, wherein the sponge hasa porous, open-cell configuration.
 15. The apparatus of claim 14,wherein the sponge has an average pore diameter greater than or equal toabout 50 microns, and wherein the porous, open-cell configurationpromotes cellular ingrowth upon placement of the sponge in the hollowanatomical structure.
 16. The apparatus of claim 13, wherein the spongehas a non-porous, closed-cell configuration.
 17. The apparatus of claim13, wherein the sponge expands radially in situ to span a cross sectionof the hollow anatomical structure.
 18. The apparatus of claim 13,wherein the sponge further comprises an additive selected from the groupconsisting of sclerosant, venoconstrictor, anti-bacterial agent, drug,anti-inflammatory agent, anti-infective agent, anesthetic,pro-inflammatory agent, cell proliferative agent, tretinoin,procoagulant, and combinations thereof.
 19. The apparatus of claim 18,wherein the procoagulant is selected from the group consisting ofcollagen, fibrinogen, fibronectin, vitronectin, laminin, thrombin,gelatin, and mixtures thereof.
 20. The apparatus of claim 1, wherein thematerial is in a form of a plug.
 21. The apparatus of claim 20, whereinthe plug is non-porous.
 22. The apparatus of claim 20, wherein the plugis configured to maintain a cross-sectional size upon placement in thehollow anatomical structure.
 23. The apparatus of claim 20, wherein theplug is formed in situ in the hollow anatomical structure.
 24. Theapparatus of claim 20, wherein the plug is pre-formed before beingplaced in the hollow anatomical structure.
 25. The apparatus of claim 1,wherein the material is in a form of a sheet, the apparatus furthercomprising an adhesive disposed on at least one of a first side of thesheet and a second side of the sheet.
 26. The apparatus of claim 1,wherein the material is in a form of a tube, the apparatus furthercomprising an adhesive disposed on at least one of an outer surface ofthe tube and an inner surface of the tube.
 27. The apparatus of claim 1,wherein the material is in a form of a rolled sheet prior to insertioninto the hollow anatomical structure, the apparatus further comprisingan adhesive disposed on at least one of a first side of the sheet and asecond side of the sheet, the sheet having an inserted configuration inwhich the sheet is at least partially unrolled.
 28. The apparatus ofclaim 1, wherein the material comprises a rod which is configured toswell upon placement in the hollow anatomical structure.
 29. Theapparatus of claim 28, wherein the rod comprises a hydrogel.
 30. A kitfor use in forming an occlusion in a hollow anatomical structure in apatient, the kit comprising: an occluding material comprising abiocompatible injectable fluid or bioabsorbable injectable fluid; andinstructions for placing an occluding material at the site, whereby anocclusion is formed in the hollow anatomical structure.
 31. The kit ofclaim 30, further comprising instructions for identifying an occlusionsite.
 32. The kit of claim 30, further comprising a delivery device forplacing the occluding material at the occlusion site, the deliverydevice comprising a needle or a catheter.